The overall purpose of Dr. O'Donnell's research during FY08 has been to investigate the epidemiology and genetic epidemiology of atherosclerotic cardiovascular disease. The major projects have emanated from the SNP Health Association Resource (SHARe), the Cohorts for Heart and Aging Research in Genome Epidemiology (CHARGE) Consortium, and a sequencing project conducted through the NHLBI's Resequencing and Genotyping (RSNG) Program. Dr. O'Donnell is the Scientific Director and Steering Committee Chair of the NHLBI's FHS SHARe Program and he is a co-founder and Steering Committee Co-chair of the CHARGE Consortium.[unreadable] [unreadable] Research Subjects: The research subjects consist primarily of participants of the Framingham Heart Study FHS original cohort, Offspring cohort and Generation 3. [unreadable] [unreadable] Phenotyping: Phenotyping consisted of: (a) usual examination measures obtained during the usual clinical examination (risk factors, anthropometric and physical examination); (b) specialized measures of circulating blood biomarkers (eg, C-reactive protein, fibrinogen, factor VII, von Willebrand factor); (c) subclinical atherosclerosis (coronary and abdominal and thoracic aortic atherosclerosis by multidetector CT imaging MDCT in 3500 Offspring and Generation 3 subjects; carotid intimal medial thickness CIMT and carotid plaque by B-mode ultrasonography in 3800 Offspring: thoracic and abdominal aortic plaque, LV mass and LV structure by cardiovascular magnetic resonance imaging CMRI in 1800); (d) clinical cardiovascular outcomes (MI, myocardial infarction; CHD, coronary heart disease; CVD, cardiovascular disease) adjudicated by a physician endpoint validation committee. [unreadable] [unreadable] Genotyping in SHARe and resequencing: Genotyping derived from two dense genomewide SNP scans, a 100K SNP scan (Affymetrix platform) in 1400 FHS Offspring and original cohort subjects and a 550K SNP scan (Affymetrix platform, 250K Nsp and 250K Sty and 50K gene-focussed MIP) in 9,400 FHS subjects from all three generations. Imputation of the 550K SNPs was conducted to 2.4 million HapMap SNPs using MACH. Additionally, sequencing was conducted by the NHLBI Resequencing and Genotyping Program of 200,000 base pairs of chromosome 9p21 in 282 FHS offspring subjects. [unreadable] [unreadable] Statistical association and linkage methods: Statistical association analyses of genotypes with phenotypes were conducted using mixed linear and/or logistic regression, generalized estimating equations, and survival analyses, when appropriate; additionally, family based association testing. Statistical linkage analyses were also conducted using SOLAR. [unreadable] [unreadable] Replication Collaboration with the Cohorts for Heart and Aging Research in Genome Epidemiology (CHARGE) Consortium: To seek strong evidence for replication, we have formed a consortium of five prospective, observational cohort studies with genomewide SNP scans and a large, common set of phenotypes. The participating cohorts include the Iceland Age, Gene/Environment Susceptibility (AGES) Study, the Cardiovascular Health Study (CHS), the Rotterdam Study (RS) and the Atherosclerosis Risk in Community (ARIC) Study. In silico replication meta-analysis is performed using a common set of 2.4 million SNPs imputed to HapMap.[unreadable] [unreadable] Research Accomplishments for Major Projects Directed by Dr. O'Donnell[unreadable] [unreadable] 1. Genetic determinants of subclinical atherosclerosis: We have completed GWAS analysis of coronary artery calcification, abdominal aortic calcification, common and internal carotid intimal medial thickness and LV mass by cardiac magnetic resonance imaging. Several genomewide significant associations have been noted. For example, SNPs in chromosome 9p21 are strongly associated with. Replication meta-analyses are underway in the CHARGE Consortium. In addition, Dr. O'Donnell is a collaborating investigator in GWAS analyses of the major CHD risk factor phenotypes: serum lipid levels, resting systolic and diastolic blood pressure, and obesity.[unreadable] [unreadable] 2. Sequencing of the chromosome 9p21 region: During FY08, resequencing was conducted in 282 FHS subjects in a 200,000 bp in the region of chromosome 9p21 implicated in MI as well as two nearby genes, CDKN2A and CDKN2B. Resequencing was completed in Sept 2008 and analysis is underway. [unreadable] [unreadable] 3. Genetic determinants of myocardial infarction/coronary heart disease: GWAS analysis has recently been conducted for incident and prevalent MI in FHS. Replication meta-analyses are underway in the CHARGE Consortium. [unreadable] [unreadable] 4. Genetic determinants of hemostatic factors and platelet aggregability: GWAS analysis has recently been conducted for circulating levels of blood fibrinogen, factor VII, and von Willebrand factor, as well as platelet aggregability to epinephrine and ADP. Several genomewide significant associations were noted. Replication meta-analyses are underway in the CHARGE Consortium. [unreadable] [unreadable] 5. Bioinformatics Tools: Our DIR bioinformatics fellow has led GWAS analyses for serum bilirubin and for platelet aggregability phenotypes. He has created an annotated database of all published GWAS associations and demonstrated its potential use for data mining. He has co-developed an informatics tool with investigators at the Broad Institute, SNAP (http://www.broad.mit.edu/mpg/snap/index.php), that is now available for widespread use for defining linkage disequilibrium relationships between any two SNPs in the genome. [unreadable] [unreadable] 6. Epidemiology of CHD risk and coronary artery calcium: We have conducted analyses to describe the distribution and epidemiology of CAC, and the potential role CAC screening has in clinical practice. We are developing an updated Framingham CHD risk score that includes CRP and family history of CHD in the model. Manuscripts for these analyses are in preparation.